approval letter: kadcyla · attention: erica j. evans, ph.d. regulat01y program management 1 dna...

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BLA 125427/0

Genentech, Inc. Attention: Erica J. Evans, Ph.D. Regulat01y Program Management 1 DNA Way South San Francisco, CA 94080-4990

Dear Dr. Evans:

Food and Drug Administration Silver Spring MD 20993

BLA APPROVAL

Please refer to your Biologics License Application (BLA) dated August 24, 2012, received August 27, 2012, submitted under section 351(a) of the Public Health Service Act for Kadcyla (ado-trastuzumab emtansine).

We acknowledge receipt of your amendments dated June 12, and 25; July 11 and 31; August 24, and 27; September 12, 18(2), 21 , 25(2), 26(2), and 28(2); October 8(2), 9(2), 11(2), 17(2), 18(2), 23(2), 24, 25, 29, 30, and 31; November 1, 2(3), 5, 6, 8(2), 12(3), 13(3), 14(2), 16, 20(2), 26, and 30(2); December 5(2), 6, 7(6), 13, 14, 19, 20, 21(2) and Janua1y 2, 3, 4, 7, 11, 15(2), 17(2), 18, 22, 23, 24,(3), 25(3), 28(2), 30(2) and Febma1y 5, 6, 7, 8, 12, and 15, 2013.

LICENSING

We have approved your BLA for Kadcyla (ado-trastuzumab emtansine) effective this date. You are hereby authorized to introduce or deliver for introduction into interstate commerce, Kadcyla (ado-trastuzumab emtansine) lmder your existing Depmi ment of Health and Human Services U.S. License No. 1048. Kadcyla (ado-trastuzumab emtansine) is indicated, as a single agent, for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, sepm·ately or in combination.

MANUFACTURING LOCATIONS

Under this license, you m·e aQ roved to manufacture ado-trastuzumab emtansine bulk dmg substance at (b)C

41, and ado-trastuzumab emtansine fmal

dmg product at (bH~Y . Drug product labeling and packaging will be done at Genentech Hillsboro FilfFiiiish Facifity m Hillsboro, Oregon.

You may label your product with the proprieta1y name, Kadcyla, and will market it as a lyophilized product in two single-use presentations of 100 mg per 15 mL vial and 160 mg per 20 mL vial.

Reference ID: 3265306

BLA 125427/0 Page2

Trastuzumab intennediate will be manufactured at Genentech, Inc., Vacaville, CA and Roche Sin~ore Technical Qperations Pte. Ltd, Sing2£ore. DMI intetmediate will be manufactured at

(b) (45.

DATING PERIOD

The dating period for ado-trastuzumab emtansine dmg product (160 mg/vial) shall be 36 months from the date of manufacture when stored at 2°C to soc. The dating period for ado-trastuzmnab emtansine dmg product (I 00 mg/vial) shall be 24 months from the date of manufacture when stored at 2°C to S°C. The date of manufacture shall be defined as the date of (b) <-11

the formulated dmg_P.roduct. The dating period for your trastuzumab intetmediate (b}(4~ The dating_.period for your ado-trastuzumab emtansine

drug substance shall be (bl <4l

We have approved the stability protocols in your license application for the purpose of extending the expiration dating period of the dmg substance and dmg product under 21 CFR 601.12. Data supp01ting extension of the expiration dating period should be submitted to the BLA Annual Rep011.

Consistent with 21 CFR 601.12, Genentech must inf01m FDA about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved application.

FDA LOT RELEASE

You are not cunently required to submit samples of future lots of ado-trastuzumab emtansine to the Center for Dmg Evaluation and Research (CDER) for release by the Director, CDER, under 21 CFR 610.2. We will continue to monitor compliance with 21 CFR 610.1, requiring completion of tests for conf01mity with standards applicable to each product prior to release of each lot.

Any changes in the manufacturing, testing, packaging, or labeling ofKadcyla (ado-trastuzumab emtansine ), or in the manufacturing facilities, will require the submission of inf01mation to your biologics license application for our review and written approval, consistent with 21 CFR 601.12.

APPROVAL & LABELING We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text.

We note that your Febmaty 13, 2013, submission includes fmal printed labeling (FPL) for your package insert. We have not reviewed this FPL. You are responsible for assuring that the wording in this printed labeling is identical to that of the approved content of labeling in the structured product labeling (SPL) f01mat.


BLA 125427/0 CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA automated drug registration and listing system (eLIST), the content of labeling [21 601.14(b)] in structured product labeling (SPL) format, as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert, text for the patient package insert, Medication Guide). Information on submitting SPL files using eLIST may be found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072392.pdf. The SPL will be accessible via publicly available labeling repositories. In addition, within 14 days of the date of this letter, amend any pending supplement that includes labeling changes for this BLA with content of labeling in SPL format to include the changes approved in this supplement. CARTON AND IMMEDIATE CONTAINER LABELS We acknowledge your January 30, 2013, submission containing final printed carton and container labels. ADVISORY COMMITTEE Your application for Kadcyla (ado-trastuzumab emtansine) was not referred to an FDA advisory committee because outside expertise was not necessary; there were no controversial issues that would benefit from advisory committee discussion. REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. We are waiving the pediatric study requirement for this application because necessary studies are impossible or highly impracticable. Breast cancer is on the list of conditions that do not occur in pediatric patients and qualify for a full waiver.


BLA 125427/0 Page4

POSTMARKETING REQUIREMENTS UNDER 505(o)

Section 505(o)(3) of the Federal Food, Dmg, and Cosmetic Act (FDCA) authorizes FDA to require holders of approved dmg and biological product applications to conduct postmarketing studies and clinical trials for certain pmposes, if FDA makes ce1tain findings required by the statute.

We have determined that an analysis of spontaneous postmarketing adverse events rep01ted under subsection 505(k)(1) of the FDCA will not be sufficient to assess signals of serious risks of emb1yo-fetal toxicity and of increased toxicity due to a variable antibody dmg ratio and to identi unexpected serious risks of increased toxicity due to (b)(

41

Furthe1more, the new phannacovigilance system that FDA is required to establish lmder section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.

Therefore, based on appropriate scientific data, FDA has dete1mined that you are required to conduct the following:

1. Establish a Pregnancy Regist:Iy to collect and analyze inf01mation for 10 years on pregnancy complications and bnth outcomes in women with breast cancer exposed to ado-u·astuzumabemtansine within 6 months of conception or during pregnancy. Submit yearly interim rep01ts, which may be included in your annual rep01ts, on the cumulative findings and analyses from the Pregnancy Regist:Iy.

The timetable you submitted on Febmmy 15, 2013, states that you will conduct this study according to the following schedule :

Draft Protocol Submission: Final Protocol Submission: Interiin Report # 1 : Interiin Rep01i #2: Interiin Rep01i #3: Interiin Report #4: Interiin Report #5: Interiin Report #6: Interiin Rep01i #7: Interiin Rep01i #8: Interiin Report #9: Study Completion: Final Rep01i Submission:


03/13 05/13 05/14 05/15 05/16 05/17 05/18 05/19 05/20 05/21 05/22 05/23 05/24

BLA 125427/0

2. Perf01m a multivariate characterization study to supp01i the implementation of a

during manufacture ofT-~~----------------------------------------~ DMI.

The timetable you submitted on Febmmy 15, 2013, states that you will conduct this study according to the following schedule:

Final Protocol Submission: Study Completion: Final Rep01i Submission:

03/13 05/13 06/13

3. Develop and validate an (b) c41method to use as a dm~bstance and dmg product regulat01y method for monitorin the (b)(

41 content and propose a specification limit for the (b)(

4 content based on clinical and commercial

batch data.


Final Protocol Submission: Study Completion: Final Rep01i Submission:

05/13 11113 12/13

4. Provide qumterly rep01is on the status of an r-------------------------------,(b}(4l

These rep01is should include, at a minimum, a sUIIllnmy of the root cause analyses, ---·.• associated con ective actions, and disposition of all affected DM1 batches. Also, provide the disposition of any potentially affected finished product batches using these affected DM1 batches. Submit an interim rep01i documenting that the manufacturing processes have been appropriately controlled at the manufacturing facilities according to Genentech 's evaluation. The interim rep01t should include a request for follow-up ins ection~. Submit a final rep01t with a statement conceming the follow-up perf01m ed on the (b)(

41 issues during the course of the FDA inspection(s), an update on whether there have been any further instances o (b)(

4\ and a proposal to prevent (bJC

41 managed by each site 's quality system.


Qumierly Rep01i # 1 : Qumierly Rep01i #2: Qumierly Rep01i #3: Qumierly Rep01i #4: Interim Report:


05/13 08/13 11113 02/14 04/14

BLA 125427/0

Quarterly Report #5: 05/14 Quarterly Report #6: 08/14 Quarterly Report #7: 11/14 Quarterly Report #8: 02/15 Final Report Submission: 04/15

Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to assess a signal of a serious risk of increased toxicity in patients with hepatic impairment. Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following: 5. Conduct a clinical trial to evaluate the impact of hepatic impairment on the pharmacokinetics

of Kadcyla (ado-trastuzumab emtansine), total trastuzumab, and DM1-containing catabolites. Based on the results of this trial, update the approved Kadcyla labeling with recommendations for appropriate use of Kadcyla in patients with hepatic impairment.

The timetable you submitted on February 15, 2013, states that you will conduct this trial according to the following schedule:

Trial Completion: 06/14 Final Report Submission: 06/15

Submit the protocol(s) to your IND 071072, with a cross-reference letter to this BLA. Submit all final report(s) to your BLA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate: “Required Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under 505(o)”, “Required Postmarketing Correspondence Under 505(o)”. Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70 requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials. FDA will consider the submission of your annual report under section 506B and 21 CFR 601.70 to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 601.70. We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.


BLA 125427/0

POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING REQUIREMENTS UNDER SECTION 506B

We remind you of your postmarketing commitments:

6. Transfer the methodology for validated dye ingress testing developed by Genentech to Conduct a study to confmn filling and crimping conditions for container closure integrity using the validated u·ansfened dye ingress method and provide a fmal rep01i in the 2014 annual rep01i.


Study Completion: 03/13 Final Rep01i Submission: 04/14

7. Conduct a study to assess the risk of,...-----------------.(b>C41

(b) (4)

usm&__~~~~----~~---~-~~--~~-~-~.--.---,~-,---0 .--~----~ the lyophilization process. Submit a fmal rep01i that includes updated specifications as a Prior Approval Supplement.


Final Rep01i Submission: 03/13

8. If (b)(4~ is observed in the dmg product after lyophilization, develop an altemative method to quantitate (bJC4l in the fmished ado-u·astuzumab emtansine dmg product after lyophilization using routine production conditions. Submit a fmal rep01i on any changes in the analytical methods as a Prior Approval Supplement.


Final Protocol Submission: 09/13 Final Rep01i Submission: 12113

9. Dedicate (bJT4J for ado-u·astuzumab emtansine dmg product manufacture

and submit a fmal rep01i of the results from (bH4Y validation and 3 media fill

simulations as a Changes Being Effected Supp ement [CBE-0).




BLA 125427/0 Page8

10. Conduct cleaning verification after each change-over prior to manufacture of ado-trastuzumab emtansine until use of (b)(41 is implemented and rep01i the updated change-over procedures in the 2014 Annuaf RepOii.


Study completion: Final Rep01i Submission:

06/13 04/14

11. Conductr----------------------------,(bn~l



12. Develop a validated, sensitive, and accurate assay for the detection ofneutmlizing antibodies to ado-trastuzumab emtansine, including procedures for accurate detection of neutmlizing antibodies to ado-tmstuzumab emtansine in the presence of ado-tmstuzmnab emtansine levels that are expected to be present in the sennn or plasma at the time of patient sampling. The assay final rep01i will be submitted as a Prior Approval Supplement by Jlme, 2015.


Final Rep01i Submission (Assay and Methodology) Date: 06/15

13. Reassess release and stability specifications for ado-tmstuzmnab emtansine dmg substance and dmg product through the end ofFebmmy 2015. Submit the final rep01i as a Changes Being Effected-30 Supplement (CBE-30).



14. Provide a material compatibility assessment r---------------~(0> <4>


BLA 125427/0

r---------------------------------.(b)(41

Provide a ~--~-~~-~-~~·~---~--~~~-toxicological risk assessment of the safety of the leachables that could be present in the DM1

inte1mediate. If significant leachables are identified during these assessments, initiate action to Initigate the source(s) of risk to product quality.

The timetable you sublnitted on Febmmy 15, 2013, states that you will conduct this study according to the following schedule:

Material Compatibility Assessment Completion: 04/13 Leachable Assessment and Toxicological Risk Assessment: 05/13 Final Rep01i Sublnission: 06/13

15. Conduct ado-trastuzumab emtansine exposure-response analyses for progression-free survival, fmal overall survival, and safety utilizing data from trial B025734/TDM4997 (TH3RESA). The results of the exposure-response analyses from both TH3RESA and B021977/TDM4370g (EMILIA) will be used to dete1mine whether a postmarketing trial is needed to optilnize the dose in patients with metastatic breast cancer who have lower exposure to ado-trastuzumab emtansine conjugate at the approved dose (3 .6 mg/kg q3w). Submit a final rep01i of the exposure-response analyses based on TH3RESA and EMILIA.

The timetable you sublnitted on Febmmy 15, 2013, states that you will conduct this study according to the following schedule:

Trial Completion: Final Rep01i Sublnission:

06/16 12116

Submit clinical protocols to your IND 071072 for this product. Sublnit nonclinical and chemisuy, manufacturing, and conu·ols protocols and all postmarketing fmal reports to this BLA. In addition, under 21 CFR 601 .70 you should include a status surnmmy of each commitment in your annual progress rep01i of postmm·keting studies to this BLA. The status sunnna1y should include expected sunnna1y completion and fmal rep01i sublnission dates, any changes in plans since the last mmual rep01i, and, for clinical studies/u·ials, number of patients entered into each study/u·ial. All submissions, including supplements, relating to these postmarketing cormnitments should be prominently labeled "Postmarketing Commitment Protocol," "Postmarketing Commitment Final Report," or "Postmarketing Commitment Correspondence."

PROMOTIONAL MATERIALS

You may request advis01y comments on proposed inu·oduct01y adveliising and promotional labeling. To do so, sublnit, in u·iplicate, a cover letter requesting advis01y comments, the


BLA 125427/0 proposed materials in draft or mock-up form with annotated references, and the package insert to:

Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266

As required under 21 CFR 601.12(f)(4), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more information about submission of promotional materials to the Office of Prescription Drug Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm. REPORTING REQUIREMENTS You must submit adverse experience reports under the adverse experience reporting requirements for licensed biological products (21 CFR 600.80). You should submit postmarketing adverse experience reports to:

Food and Drug Administration Center for Drug Evaluation and Research Central Document Room 5901-B Ammendale Road Beltsville, MD 20705-1266

Prominently identify all adverse experience reports as described in 21 CFR 600.80. You must submit distribution reports under the distribution reporting requirements for licensed biological products (21 CFR 600.81). You must submit reports of biological product deviations under 21 CFR 600.14. You should promptly identify and investigate all manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution. If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulation, you must submit a report on Form FDA-3486 to:

Food and Drug Administration Center for Drug Evaluation and Research Division of Compliance Risk Management and Surveillance 5901-B Ammendale Road Beltsville, MD 20705-1266


BLA 125427/0

Biological product deviations, sent by courier or overnight mail, should be addressed to:

Food and Drug Administration Center for Drug Evaluation and Research Division of Compliance Risk Management and Surveillance 10903 New Hampshire Avenue, Bldg. 51, Room 4206 Silver Spring, MD 20903

MEDWATCH-TO-MANUFACTURER PROGRAM The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm. POST-ACTION FEEDBACK MEETING New molecular entities and new biologics qualify for a post-action feedback meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, call the Regulatory Project Manager for this application. If you have any questions, call Lisa Skarupa, Regulatory Project Manager, at (301) 796-2219.

Sincerely,

{See appended electronic signature page}

Richard Pazdur, M.D. Director Office of Hematology and Oncology Products Center for Drug Evaluation and Research

ENCLOSURE(S):

Content of Labeling Carton and Container Labeling


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

RICHARD PAZDUR02/22/2013


approval letter: kadcyla · attention: erica j. evans, ph.d. regulat01y program management 1 dna...

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